The present invention relates to certain novel quinoline derivatives as well as to their use as pharmaceuticals, in particular as inhibitors of specific kinase enzymes, in particular MEK enzymes. Further aspects of the invention include pharmaceutical compositions and methods of treatment of proliferative disease such as cancer using said compounds.
Cancer is a disease in which cells grow and divide in an uncontrolled fashion. This uncontrolled growth arises from abnormalities in signal transduction pathways that are used by normal cells to regulate cell growth and division in response to various signalling molecules. Normal cells do not proliferate unless stimulated to do so by specific signal molecules located outside the cell derived from nearby cells or tissues. Growth factors bind to the cell membrane via specific receptors which have intrinsic enzyme activity. These receptors relay the growth signal to the cell nucleus via a series of signalling proteins. In cancer, a number of defects in signal pathways are apparent. For example, cancer cells may produce their own growth factors which bind to their cognate receptors, resulting in an autocrine loop, or receptors may be mutated or overexpressed leading to an increased, continuous signal to proliferate. In addition, negative regulators of cell growth may be lost.
Oncogenes are cancer related genes which often encode abnormal versions of signal pathway components, such receptor tyrosine kinases, serine-threonine kinasem or downstream signaling molecules such as the ras genes, which code for closely related small guanine nucleotide binding proteins which hydrolyse bound guanosine triphosphate (GTP) to guanosine diphosphate (GDP). Ras proteins are active in promoting cell growth and transformation when they are bound to GTP and inactive when they are bound to GDP. Transforming mutants of p21ras are defective in their GTPase activity and hence remain in the active GTP bound state. The ras oncogene is known to play an integral role in certain cancers, and has been found to contribute to the formation of over 20% of all cases of human cancer.
When activated by ligand, cell surface receptors which are coupled to the mitogenic response, such as growth factor receptors, initiate a chain of reactions which leads to the activation of guanine nucleotide exchange activity on ras. When in its active GTP-bound state, a number of proteins interact directly with ras at the plasma membrane resulting in signal transmission through several distinct pathways. The best characterised effector protein is the product of the raf proto-oncogene. The interaction of raf and ras is a key regulatory step in the control of cell proliferation. Ras-mediated activation of the raf serine-threonine kinase in turn activates the dual-specificity MEK (MEK1 and MEK2), which is the immediate upstream activator of mitogen activated protein kinase (MAPKs known as extracellular signal regulated protein kinases or ERK1 and ERK2). To date, no substrates of MEK other than MAPK have been identified, though recent reports indicate that MEK may also be activated by other upstream signal proteins such as MEK kinase or MEKK1 and PKC. Activated MAPK translocates and accumulates in the nucleus, where it can phosphorylate and activate transcription factors such as Elk-1 and Sap1a, leading to the enhanced expression of genes such as that for c-fos.
The ras-dependent raf-MEK-MAPK cascade is one of the key signalling pathways responsible for transmitting and amplifying mitogenic signals from cell surface to the nucleus resulting in changes in gene expression and cell fate. This ubiquitous pathway appears essential for normal cell proliferation and constitutive activation of this pathway is sufficient to induce cellular transformation. Transforming mutants of p21ras are constitutively active, resulting in raf, MEK and MAPK activity and cell transformation. Inhibition of MEK activity using either antisense raf, a dominant negative MEK mutant or the selective inhibitor PD098059 have been shown to block the growth and morphological transformation of ras-transformed fibroblasts.
The mechanism of activation of raf, MEK and MAPK is through phosphorylation on specific serene, threonine or tyrosine residues. Activated raf and other kinases phosphorylate MEK1 on S218 and S222 and MEK2 on S222 and S226. This results in MEK activation and subsequent phosphorylation and activation of ERK1 on T190 and Y192 and ERK2 on T183 and Y185 by the dual specificity MEKs. Whilst MEK can be activated by a number of protein kinases, and active MAPKs phosphorylate and activate a number of substrate proteins including transcription factors and other protein kinases, MEKs appear specific and sole activators of MAPKs and could act as a focal point for cross-cascade regulation. MEK1 and MEK2 isoforms show unusual specificity and also contain a proline-rich insert between catalytic subdomains IX and X which is not present in any of the other known MEK family members. These differences between MEK and other protein kinases, together with the known role of MEK in proliferative signalling suggest that it may be possible to discover and employ selective MEK inhibitors as therapeutic agents for use in proliferative disease.
WO 98/43960 discloses a range of 3-cyano quinoline compounds and their use in the treatment of cancer. Certain of the compounds are demonstrated as being inhibitors of Epidermal Growth Factor Receptor Kinase, and to inhibit cancer cell growth. Other quinoline derivatives which inhibit the effect of growth factors such as VEGF are described in WO98/13350.
The conformations of certain diquinolinyl sulfides have been studied by NMR and reported by Wyszomirski et al in Phosphorus, Sulphur and Silicon, 1994, vol 95-96, pg 415-416. Methods of making specific quinoline derivatives are described by Atkins et al in Organic Process Research and Development, 1997, vol 1, pg 185-197. The use of certain quinoline derivatives as gastric (H+/K+)xe2x80x94ATPase inhibitors and as fungicides are described by Ife et al in J Med Chem, 1992, vol 35, pg 3413-3422 and in EP 326330 respectively.
This invention provides compounds which are inhibitors of the kinase activity of MEK and as a result, can produce therapeutically useful effects in the treatment of proliferative disease and in particular cancer.
According to the present invention there is provided a compound of formula (I) 
or a pharmaceutically acceptable salt thereof; for use as a medicament wherein:
n is 0-1;
Y is selected from xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NR7xe2x80x94 where R7 is alkyl of 1-6 carbon atoms
R5 is chloro or bromo;
Y is selected from xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NR7xe2x80x94 where R7 is alkyl of 1-6 carbon atoms
R6 is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl of 1 to 6 carbon atom groups; or is a pyridinyl, pyrimidinyl, or phenyl ring;
wherein the pyridinyl, pyrimidinyl, or phenyl ring may be substituted with one, two or three groups selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenyl, benzoyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, and benzoylamino; or two adjacent substitutents on said phenyl, pyridyl or pyrimidinyl ring may be joined together to form a fused ring, which ring may be aromatic or non-aromatic in character and which may contain further heteroatoms;
or R6 is a group xe2x80x94R8xe2x80x94Xxe2x80x94R9 where
R8 is a divalent cycloalkyl of 3 to 7 carbon atoms, which may be optionally further substituted with one or more alkyl of 1 to 6 carbon atom groups; or is a divalent pyridinyl, pyimidinyl, or phenyl ring; wherein the pyridinyl, pyrimidinyl, or phenyl ring may be optionally further substituted with one or more groups selected from halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, and benzoylamino;
where X is selected from CH2, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, CH2 or xe2x80x94NR5xe2x80x94 where R5 is alkyl of 1-6 carbon atoms, and
R9 is a group (CH2)mR10 where m is 0, or an integer of from 1-3 and R10 is an optionally substituted aryl or optionally substituted cycloalkyl ring of up to 10 carbon atoms, or R10 is a heterocyclic ring containing 1 or 2 oxygen atoms and optionally one or more substitutents; R1, R2, R3 and R4 are each independently selected from hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C1-3alkyl, xe2x80x94NR11R12 (wherein R11 and R12, which may be the same or different, each represents hydrogen or C1-3alkyl), or a group R13xe2x80x94X1xe2x80x94(CH2)x wherein x is 0 to 3, X1 represents xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94OCOxe2x80x94, carbonyl, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR14COxe2x80x94, xe2x80x94CONR15xe2x80x94, xe2x80x94SO2NR16xe2x80x94, xe2x80x94NR17SO2xe2x80x94 or xe2x80x94NR18xe2x80x94 (wherein R14, R15, R16, R17 and R18 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R13 is selected from one of the following sixteen groups:
1) C1-5alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro and amino;
2) C1-5alkylX2COR19 (wherein X2 represents xe2x80x94Oxe2x80x94 or xe2x80x94NR20xe2x80x94 (wherein R20 represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R19 represents xe2x80x94NR21R22xe2x80x94 or xe2x80x94OR23xe2x80x94 (wherein R21, R22 and R23 which may be the same or different each represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl));
3) C1-5alkylX3R24 (wherein X3 represents xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94NR25COxe2x80x94, xe2x80x94CONR26xe2x80x94, xe2x80x94SO2NR27xe2x80x94, xe2x80x94NR28SO2xe2x80x94 or xe2x80x94NR29xe2x80x94 (wherein R25, R26, R27, R28 and R29 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R24 represents hydrogen, C1-3alkyl, cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which C1-3alkyl group may bear one or two substituents selected from oxo, hydroxy, halogeno and C1-4alkoxy and which cyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl and C1-4alkoxy);
4) C1-5alkylX4C1-5alkylX5R30 (wherein X4 and X5 which may be the same or different are each xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR31COxe2x80x94, xe2x80x94CONR32xe2x80x94, xe2x80x94SO2NR33xe2x80x94, xe2x80x94NR34SO2xe2x80x94 or xe2x80x94NR35xe2x80x94 (wherein R31, R32, R33, R34 and R35 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R30 represents hydrogen or C1-3alkyl);
5) C1-5alkylR36 (wherein R36 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl and C1-4alkoxy);
6) (CH2)qX6R37 (wherein q is an integer from 0 to 5, X6 represents a direct bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR38COxe2x80x94, CONR39xe2x80x94, xe2x80x94SO2NR40xe2x80x94, xe2x80x94NR41SO2xe2x80x94 or xe2x80x94NR42xe2x80x94 (wherein R38, R39, R40, R41 and R42 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R37 is a phenyl group, a pyridone group or a 5 or 6 membered aromatic heterocyclic group with 1 to 3 heteroatoms selected from O, N and S, which phenyl, pyridone or aromatic heterocyclic group may carry up to 5 substituents selected from hydroxy, halogeno, amino, C1-4alkyl, C1-4alkoxy, C1-4hydroxyalkyl, C1-4hydroxyalkoxy, C1-4aminoalkyl, C1-4alkylamino, carboxy, cyano, xe2x80x94CONR43R44 and xe2x80x94NR45COR46 (wherein R43, R44, R45 and R46, which may be the same or different, each represents hydrogen, C1-4alkyl or C1-3alkoxyC2-3alkyl));
7) C2-6alkenylR36 (wherein R36 is as defined hereinbefore);
8) C2-6alkynylR36 (wherein R36 is as defined hereinbefore);
9) X7R47 (wherein X7 is xe2x80x94SO2xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94CONR48R49xe2x80x94 (wherein R48 and R49, which may be the same or different, each represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R47 represents C1-5alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro and amino) with the provisos that when X7 is xe2x80x94SO2xe2x80x94, X1 is xe2x80x94Oxe2x80x94, when X7 is xe2x80x94Oxe2x80x94, X1 is carbonyl, when X7 is xe2x80x94CONR48R49xe2x80x94, X1 is xe2x80x94Oxe2x80x94 or NR18 (wherein R48, R49 and R18 are as defined hereinbefore);
10) C2-6alkenylR37 (wherein R37 is as defined hereinbefore);
11) C2-6alkynylR37 (wherein R37 is as defined hereinbefore);
12) C2-6alkenylX8R37 (wherein X8 represents xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR50COxe2x80x94, xe2x80x94CONR51xe2x80x94, xe2x80x94SO2NR52xe2x80x94, xe2x80x94NR53SO2xe2x80x94 or xe2x80x94NR54xe2x80x94 (wherein R50, R51, R52, R53 and R54 each independently represents hydrogen, C1-3alkyl or C1-3 alkoxyC1-3alkyl) and R37 is as defined hereinbefore);
13) C2-6alkynylX9R37 (wherein X9 represents xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR55COxe2x80x94, xe2x80x94CONR56xe2x80x94, xe2x80x94SO2NR57xe2x80x94, xe2x80x94NR58SO2xe2x80x94 or xe2x80x94NR59xe2x80x94 (wherein R55, R56, R57, R58 and R59 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R37 is as defined hereinbefore);
14) C1-3alkylX10C1-3alkylR37 (wherein X10 represents xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR60COxe2x80x94, xe2x80x94CONR61xe2x80x94, xe2x80x94SO2NR62xe2x80x94, xe2x80x94NR63SO2xe2x80x94 or xe2x80x94NR64xe2x80x94 (wherein R60, R61, R62, R63 and R64 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R37 is as defined hereinbefore);
15) R36 (wherein R36 is as defined hereinbefore); and
16) C1-3alkylX10C1-3alkylR36 (wherein X10 and R36 are as defined hereinbefore).
In particular the invention provides a compound of formula (I) as shown above or a pharmaceutically acceptable salt thereof; for use as a medicament wherein:
n is 0-1;
Y is selected from xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NR7xe2x80x94 where R7 is alkyl of 1-6 carbon atoms
R5 is chloro or bromo;
Y is selected from xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NR7xe2x80x94 where R7 is alkyl of 1-6 carbon atoms
R6 is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl of 1 to 6 carbon atom groups; or is a pyridinyl, pyrimidinyl, or phenyl ring;
wherein the pyridinyl, pyrimidinyl, or phenyl ring may be optionally mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of3-8 carbon atoms, and benzoylamino;
or R6 is a group xe2x80x94R8xe2x80x94Xxe2x80x94R9 where
R8 is a divalent cycloalkyl of 3 to 7 carbon atoms, which may be optionally further substituted with one or more alkyl of 1 to 6 carbon atom groups; or is a divalent pyridinyl, pyimidinyl, or phenyl ring; wherein the pyridinyl, pyrimidinyl, or phenyl ring may be optionally further substituted with one or more groups selected from halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, and benzoylamino;
where X is selected from xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, CH2 or xe2x80x94NRaxe2x80x94 where Ra is alkyl of 1-6 carbon atoms, and
R9 is a group (CH2)mR10 where m is 0, or an integer of from 1-3 and R10 is an optionally substituted aryl or optionally substituted cycloalkyl ring of up to 10 carbon atoms, or R10 is a heterocyclic ring containing 1 or 2 oxygen atoms and optionally one or more substitutents;
R1, R2, R3 and R4 are each independently selected from hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C1-3alkyl, xe2x80x94NR11R12 (wherein R11 and R12, which may be the same or different, each represents hydrogen or C1-3alkyl), or a group R13xe2x80x94X1xe2x80x94(CH2)x wherein x is 0 to 3, X1 represents xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94OCOxe2x80x94, carbonyl, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR14COxe2x80x94, xe2x80x94SO2NR16xe2x80x94, xe2x80x94NR17SO2xe2x80x94 or xe2x80x94NR18xe2x80x94 (wherein R14, R15, R16, R17 and R18 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R13 is selected from one of the sixteen groups defined above.
Suitable pharmaceutically acceptable salts of compounds of formula (I) include acid addition salts such as methanesulfonate, fumarate, hydrochloride, hydrobromide, citrate, maleate and salts formed with phosphoric and sulphuric acid. A preferred pharmaceutically acceptable salt is a hydrochloride salt.
The alkyl portion of the alkyl, alkoxy, alkanoyloxy, alkoxymethyl, alkanoyloxymethyl, alkylsuphinyl, alkylsulphonyl, alkylsulfonamido, carboalkoxy, carboalkyl, alkanoylamino aminoalkyl, alkylaminoalkyl, N,N-dicycloalkylaminoalkyl, hydroxyalkyl, and alkoxyalkyl substituents include both straight chain as well as branched carbon chains. The cycloalkyl portions of N-cycloalkyl-N-alkylaminoalkyl and N,N-dicycloalkylaminoalkyl substituents include both simple carbocycles as well as carbocycles containing alkyl substituents. The alkenyl portion of the alkenyl, alkenoyloxymethyl, alkenyloxy, alkenylsulfonamido, substituents include both straight chain as well as branched carbon chains and one or more sites of unsaturation. The alkynyl portion of the alkynyl, alkynoyloxymethyl, alkynylsulfonamido, alkynyloxy, substituents include both straight chain as well as branched carbon chains and one or more sites of unsaturation. Carboxy is defined as a xe2x80x94CO2H radical. Carboalkoxy of 2-7 carbon atoms is defined as a xe2x80x94CO2Rxe2x80x3 radical, where Rxe2x80x3 is an alkyl radical of 1-6 carbon atoms. Carboalkyl is defined as a xe2x80x94CORxe2x80x3 radical, where Rxe2x80x3 is an alkyl radical of 1-6 carbon atoms. Alkanoyloxy is defined as a xe2x80x94OCORxe2x80x3 radical, where Rxe2x80x3 is an alkyl radical of 1-6 carbon atoms. Alkanoyloxymethyl is defined as Rxe2x80x3CO2CH2xe2x80x94 radical, where Rxe2x80x3 is an alkyl radical of 1-6 carbon atoms. Alkoxymethyl is defined at Rxe2x80x3OCH2xe2x80x94 radical, where Rxe2x80x3 is an alkyl radical of 1-6 carbon atoms. Alkyl sulphinyl is defined as Rxe2x80x3SOxe2x80x94 radical, where Rxe2x80x3 is an alkyl radical of 1-6 carbon atoms. Alkylsulphonyl is defined as Rxe2x80x3SO2xe2x80x94 radical, where Rxe2x80x3 is alkyl radical of 1-6 carbon atoms. Alkylsulfonamido, alkenylsulfonamido, alkynylsulfonamido are defined as Rxe2x80x3SO2NHxe2x80x94 radical, where Rxe2x80x3 is an alkyl radical of 1-6 carbon atoms, an alkenyl radical of 2-6 carbon atoms, or an alkynyl radical of 2-6 carbon atoms, respectively. N-alkylcarbamoyl is defined as Rxe2x80x3NHCOxe2x80x94 radical, where Rxe2x80x3 is an alkyl radical of 1-6 carbon atoms. N,N-dialkylcarbamoyl is defined as Rxe2x80x3 Rxe2x80x2NCOxe2x80x94 radical, where Rxe2x80x3 is an alkyl radical of 1-6 carbon atoms, Rxe2x80x2 is an alkyl radical of 1-6 carbon atoms and Rxe2x80x2, and Rxe2x80x3 may be the same or different. When X is substituted, it is preferred that it is mono-, di-, or tri-substituted, with monosubstituted being most preferred. It is preferred that of the substituents, R1, R2, R3 and R4 at least one is hydrogen and it is most preferred that two or three be hydrogen. An azacycloalkyl-N-alkyl substituent refers to a monocyclic heterocycle that contains a nitrogen atom on which is substituted a straight or branched chain alkyl radical. A morpholino-N-alkyl substituent is a morpholine ring substituted on the nitrogen atom with a straight or branch chain alkyl radical. A piperidino-N-alkyl substituent is a piperidine ring substituted on one of the nitrogen atoms with a straight or branch chain alkyl radical. A N-alkyl-piperazino-N-alkyl substituent is a piperazine ring substituted on one of the nitrogen atoms with a straight or branched chain alkyl group and on the other nitrogen atom with a straight or branch chain alkyl radical.
When any group contains an alkyl portion, the alkyl portion contains preferably 1-6 carbon atoms, more preferably 1-4 carbon atoms, particularly methyl, ethyl, n-propyl iso-propyl, n-butyl, iso-butyl, sec-butyl or tert-butyl. When any group contains an alkenyl or alkynyl portion, the alkenyl or alkynyl portion contains preferably 2-6 carbon atoms, more preferably 2-4 carbon atoms.
The term xe2x80x9carylxe2x80x9d used herein includes aromatic carbocyclic compounds, for example of from 6 to 20 atoms such as phenyl or naphthyl. The term xe2x80x9cheterocyclicxe2x80x9d refers to ring structures suitably from 5 to 20 atoms in size, up to four of which are heteroatoms such as oxygen, sulphur and nitrogen. The ring structures may be monocyclic, bi- or tricyclic and be aromatic or non-aromatic in character including the possibility that part of a ring system has aromatic character whilst other part(s) do not.
The compounds of this invention may contain an asymmetric carbon; in such cases, the compounds of this invention cover the racemate and the individual R and S entantiomers, and in the case where more than one asymmetric carbon exists, the individual diasteromers, their racemates and individual entantiomers.
Preferably Y is xe2x80x94NHxe2x80x94.
Preferably R5 is chloro.
Suitably Ra is phenyl, pyridyl or pyrimidinyl, and preferably phenyl which are optionally substituted as defined above. Suitable substituents include halo such as chloro or fluoro, hydroxy or benzoyl.
When two adjacent substitutents on said phenyl, pyridyl or pyrimidinyl ring are be joined together to form a fused ring, the ring is suitably a 5 or 6 membered aromatic ring, and preferably a 5 membered ring which includes at least one heteroatom such as nitrogen. Particular examples of groups Ra are indole, benzimidazole, or indazole.
In a preferred embodiment, the group R6 is a group xe2x80x94R8xe2x80x94Xxe2x80x94R9 where R8, X and R9 are as defined above. Suitably X is oxygen.
Preferably n is 0.
Examples of optional substituents for groups R10 include one or more groups selected from hydroxy; halo; nitro; cyano; carboxy; C1-6alkoxy; C1-6alkyl; C2-6alkenyl; C2-6alkynyl; C2-6alkenyloxy; C2-6alkynyloxy; C3-6cycloalkyl; amino; mono- or di-C1-6alkyl amino; heterocyclyl optionally substituted with C1-4alkyl or oxo; C(O)Ra, C(O)ORa, S(O)dRa; NRaC(O)Rb; C(O)NRaS(O)dRb, C(O)NRaRb;; NRaC(O)NRbRc; NRaS(O)dRb or N(S(O)dRb)S(O)dRc where d is 0, 1 or 2 and Ra, Rb and Rc are independently selected from hydrogen, C1-6alkyl, aryl, C3-6cycloalkyl or heterocylcyl, and wherein any alkyl, alkenyl or alkynyl group or moiety contained within the substituent one R10 may themselves be optionally substituted with one or more groups selected from hydroxy; cyano; nitro; halo; carboxy; carboalkoxy of 2-7 carbon atoms, C3-6cycloalkyl, heterocyclyl optionally substituted with C1-6alkyl or oxo; C(O)Rd, C(O)ORdNRdRe, S(O)eRd, NRdC(O)Re; C(O)NRdRe; NRdC(O)NReRf; NRdS(O)eRe where e is 0, 1 or 2 and Rd, Re and Rf are independently selected from hydrogen or C1-6alkyl optionally substituted with one or more groups selected from hydroxy; cyano; nitro; halo; carboxy; carboalkoxy of 2-7 carbon atoms, C3-4cycloalkyl, heterocyclyl optionally substituted with C1-6alkyl or oxo; C(O)Rg, C(O)ORgNRgRh, S(O)eRg, NRhC(O)Rg; C(O)NRgRh; NRgC(O)NRhRi; NRgS(O)eRh where e is as defined above and Rg, Rh and Ri are independently selected from hydrogen or C1-6alkyl. Alternatively, two substituents on adjacent atoms may be joined to form the second ring of a bicyclic ring system wherein the said second ring is optionally substituted with one or more of the groups listed above for R10 and optionally contains one or more heteroatoms.
In some embodiments, the level of substitution on the group R10 is a chain substituted with a complex substituent. Thus, for example, a substituent may comprise an subsituted alkyl chain which is optionally interposed with heteroatoms such as groups of sub-formula (i)
xe2x80x94Xaxe2x80x94R70xe2x80x94(Xbxe2x80x94R71)qxe2x80x94(Xc)sxe2x80x94R72xe2x80x83xe2x80x83(i)
where Xa, Xb and Xc are independently selected from any of the groups listed above for Xxe2x80x2,
R70 and R71 are independently selected from C1-4alkylene, C2-4alkenylene or C2-4alkynylene groups any of which may be optionally substituted with hydroxy; cyano; nitro; halo; carboxy, carboalkoxy of 2-7 carbon atoms or C3-4cycloalkyl;
R72 is hydrogen or an C1-4alkyl, C2-4 alkenyl or C2-4alkynyl group any of which may be optionally substituted with hydroxy; cyano; nitro; halo; carboxy or C3-4cycloalkyl;
and q and s are independently 0 or 1.
Particular examples of groups R10 include phenyl or cycloalkyl of from 3-8 and preferably of 6 carbon atoms which are substituted at the position alpha with a alkoxy group, in particular methoxy.
When R10 is substituted phenyl or cycloalkyl, m is preferably 0.
Examples of heterocyclic rings R10 include 3-7 membered rings, up to two of which may be oxygen atoms. Such groups include: 
where each R65 is independently selected from hydrogen or C1-6alkyl and especially methyl. In such compounds, m is suitably 1, 2 or 3.
Suitable further substitutents for R8 include those listed above for pyridyl, pyrimidinyl and phenyl groups R6.
Thus a preferred sub-group of compounds of formula (I) are compounds of formula (II) 
where R1, R2, R3, R4 and R5 are as defined above and R66 is C1-6 alkyl in particular methyl and R67 is selected from hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, and benzoylamino.
Preferably R67 is hydrogen.
Examples of preferred groups for R1, R2, R3 and R4 are set out in WO 98/13350. Preferably x is 0. Conveniently R13 is selected from one of the following sixteen groups:
1) C1-5alkyl which may be unsubstituted or substituted with one or more fluorine atoms, or C2-5alkyl which may be unsubstituted or substituted with one or more groups selected from hydroxy and amino;
2) C2-3alkylX2COR19 (wherein X2 is as defined hereinbefore and R19 represents xe2x80x94NR21R22xe2x80x94 or xe2x80x94OR23xe2x80x94 (wherein R21, R22 and R23 which may be the same or different each represents hydrogen, C1-2alkyl or C1-2alkoxyethyl));
3) C2-4alkylX3R24 (wherein X3 is as defined hereinbefore and R24 represents hydrogen, C1-3alkyl, cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which C1-3alkyl group may bear one or two substituents selected from oxo, hydroxy, halogeno and C1-3alkoxy and which cyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-3alkyl, C1-3hydroxyalkyl and C1-3alkoxy);
4) C2-3alkylX4C2-3alkylX5R30 (wherein X4 and X5 are as defined hereinbefore and R30 represents hydrogen or C1-3alkyl);
5) C1-5alkylR70 (wherein R70 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to C1-5alkyl through a carbon atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-3alkyl, C1-3hydroxyalkyl and C1-3alkoxy) or C2-5alkylR71 (wherein R71 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms of which one is N and the other is selected independently from O, S and N, which heterocyclic group is linked to C2-5alkyl through a nitrogen atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-3alkyl, C1-3hydroxyalkyl and C1-3alkoxy);
6) (CH2)qX6R37 (wherein X6 is as defined hereinbefore; q is an integer from 0 to 4 if X6 is a direct bond and q is 0, 2 or 3 if X6 is other than a direct bond; and R37 is a phenyl group, a pyridone group or a 5 or 6 membered aromatic heterocyclic group with 1 to 3 heteroatoms selected from O, N and S, of which preferably one is N, which phenyl group, pyridone group or aromatic heterocyclic group may be substituted as hereinbefore defined, advantageously substituted with up to 2 substituents as hereinbefore defined, more preferably substituted with one substituent selected from the group of substituents as hereinbefore defined);
7) C4-5alkenylR72 (wherein R72 represents R70 or R71 as defined hereinbefore);
8) C4-5alkylR72 (wherein R72 represents R70 or R71 as defined hereinbefore);
9) X7R47 (wherein X7 is as defined hereinbefore and R47 represents C1-3alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro and amino);
10) C3-5alkenylR37 (wherein R37 is as defined hereinbefore);
11) C3-5alkynylR37 (wherein R37 is as defined hereinbefore);
12) C4-5alkenylX8R37 (wherein X8 and R37 are as defined hereinbefore);
13) C4-5alkynylX9R30 (wherein X9 and R30 are as defined hereinbefore);
14) C1-3alkylX10C1-3alkylR37 (wherein X10 and R37 are as defined hereinbefore);
15) R36 (wherein R36 is as defined hereinbefore); and
16) C1-3alkylX11C1-3alkylR36 (wherein X11 and R36 are as defined hereinbefore).
Advantageously R13 is selected from one of the following eleven groups:
1) C1-4alkyl which may be unsubstituted or substituted with one or more fluorine atoms, or C2-4alkyl which may be unsubstituted or substituted with one or two groups selected from hydroxy and amino;
2) C2-3alkylX2COR19 (wherein X2 is as defined hereinbefore and R19 represents xe2x80x94NR21R22xe2x80x94 or xe2x80x94OR23xe2x80x94 (wherein R21, R22 and R23 which may be the same or different each represents hydrogen, C1-2alkyl or C1-2alkoxyethyl));
3) C2-3alkylX3R24 (wherein X3 is as defined hereinbefore and R24 is a group selected from C1-3alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl which group is linked to X3 through a carbon atom and which C1-3alkyl group may bear one or two substituents selected from oxo, hydroxy, halogeno and C1-3alkoxy and which cyclopentyl, cyclohexyl, pyrrolidinyl or piperidinyl group may carry one substituent selected from oxo, hydroxy, halogeno, C1-2alkyl, C1-2hydroxyalkyl and C1-2alkoxy);
4) C2-3alkylX4C2-3alkylX5R30 (wherein X4 and X5 are as defined hereinbefore) and R30 represents hydrogen or C1-2alkyl);
5) C1-4alkylR70 (wherein R70 is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl and 1,3dithian-2-yl, which group is linked to C1-4alkyl through a carbon atom and which group may carry one or two substituents selected from oxo, hydroxy, halogeno, C1-2alkyl, C1-2hydroxyalkyl and C1-2alkoxy) or C2-4alkylR71 (wherein R71 is a group selected from morpholino, thiomorpholino, pyrrolidin-1-yl, piperazin-1-yl and piperidino which group may carry one or two substituents selected from oxo, hydroxy, halogeno, C1-2alkyl, C1-2hydroxyalkyl and C1-2alkoxy); and
6) (CH2)qX6R37 (wherein X6 is as defined hereinbefore; q is an integer from 1 to 3 if X6 is a direct bond and q is 2 or 3 if X6 is other than a direct bond; and R37 is a phenyl group, a pyridone group or a 5 or 6 membered aromatic heterocyclic group with 1 to 2 heteroatoms selected from O, N and S, of which preferably one is N, which phenyl group, pyridone group or aromatic heterocyclic group may be substituted as hereinbefore defined, preferably substituted with one substituent selected from hydroxy, halogeno, C1-2alkyl, C1-2alkoxy, C1-2hydroxyalkyl, C1-2hydroxyalkoxy, carboxy, cyano, xe2x80x94CONR43R44 and xe2x80x94NR45COR46 (wherein R43, R44, R45 and R46, which may be the same or different, each represents hydrogen or C1-2alkyl));
7) C4-5alkenylR71 (wherein R71 is as defined hereinbefore);
8) C4-5alkynylR71 (wherein R71 is as defined hereinbefore);
9) C1-3alkylX10C1-3alkylR37 (wherein X10 and R37 are as defined hereinbefore);
10) R36 (wherein R36 is as defined hereinbefore); and
11) C1-3alkylX11C1-3 alkylR36 (wherein X11 and R36 are as defined hereinbefore).
Preferably R13 is selected from one of the following nine groups:
1) C1-3alkyl which may be unsubstituted or substituted with one or more fluorine atoms, or C2-3alkyl which may be unsubstituted or substituted with one or two groups selected from hydroxy and amino;
2) 2-(3,3-dimethylureido)ethyl, 3-(3,3-dimethylureido)propyl, 2-(3-methylureido)ethyl, 3-(3-methylureido)propyl, 2-ureidoethyl, 3-ureidopropyl 2(N,N-dimethylcarbamoyloxy)ethyl, 3-(N,N-dimethylcarbamoyloxy)propyl, 2-(N-methylcarbamoyloxy)ethyl, 3-(N-methylcarbamoyloxy)propyl, 2-(carbamoyloxy)ethyl, 3-(carbamoyloxy)propyl;
3) C2-3alkylX3R24 (wherein X3 is as defined hereinbefore and R24 is a group selected from C1-2alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl which group is linked to X3 through a carbon atom and which C1-2alkyl group may bear one or two substituents selected from oxo, hydroxy, halogeno and C1-2alkoxy and which cyclopentyl, cyclohexyl, pyrrolidinyl or piperidinyl group may carry one substituent selected from oxo, hydroxy, halogeno, C1-2alkyl, C1-2hydroxyalkyl and C1-2alkoxy);
4) C2-3alkylX4C2-3alkylX5R32 (wherein X4 and X5 are as defined hereinbefore) and R30 represents hydrogen or C1-2alkyl);
5) C1-2alkylR70 (wherein R70 is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl and 1,3-dithian-2-yl, which group is linked to C1-2alkyl through a carbon atom and which group may carry one substituent selected from oxo, hydroxy, halogeno, C1-2alkyl, C1-2hydroxyalkyl and C1-2alkoxy) or C2-3alkylR59 (wherein R59 is a group selected from morpholino, thiomorpholino, piperidino, piperazin-1-yl and pyrrolidin-1-yl which group may carry one or two substituents selected from oxo, hydroxy, halogeno, C1-2alkyl, C1-2hydroxyalkyl and C1-2alkoxy);
6) (CH2)qX6R37 (wherein X6 is as defined hereinbefore; q is an integer from 1 to 3 if X6 is a direct bond and q is 2 or 3 if X6 is other than a direct bond; and R37 is a group selected from phenyl, a pyridone group, pyridyl, imidazolyl, thiazolyl, thienyl, triazolyl and pyridazinyl, preferably selected from phenyl, a pyridone group, pyridyl, imidazolyl, thiazolyl and triazolyl which group may be substituted with one substituent selected from hydroxy, halogeno, C1-2alkyl, C1-2alkoxy, C1-2hydroxyalkyl, C1-2hydroxyalkoxy, carboxy, cyano, xe2x80x94CONR43R44 and xe2x80x94NR45COR46 (wherein R43, R44, R45 and R46 are as defined hereinbefore);
7) C1-3alkylX10C1-3alkylR37 (wherein X10 and R37 are as defined hereinbefore);
8) R36 (wherein R36 is as defined hereinbefore); and
9) C1-3alkylX11C1-3alkylR36 (wherein X11 and R36 are as defined hereinbefore). More preferably R13 represents 2-(methylthiazol-4-ylmethyl, 2-acetamidothiazol4-ylmethyl, 1-methylimidazol-2-ylmethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl, 3-(4-pyridyl)propyl, 2-((N-(1-methylimidazol-4-ylsulphonyl)-N-methyl)amino)ethyl, 2-((N-(3-morpholinopropylsulphonyl)-N-methyl)amino)ethyl, 2-((N-methyl-N4-pyridyl)amino)ethyl, 2-(4-oxidomorpholino)ethyl, 3-(4-oxidomorpholino)propyl, 2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl, 3-(4-oxo-1,4-dihydro-1-pyridyl)propyl, methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-(N,N-dimethylsulphamoyl)ethyl, 2(N-methylsulphamoyl)ethyl, (1,3-dioxolan-2-yl)methyl, 2-(1,3-dioxolan-2-yl)ethyl, 2-(2-methoxyethylamino)ethyl, 2-(2-hydroxyethylamino)ethyl, 3-(2-(2-methoxyethylamino)propyl, 3-(2-hydroxyethylamino)propyl, 2-(1,2,4-triazol-1yl)ethyl, 2-(1,2,4-triazol-4-yl)ethyl, 3-(1,2,4-triazol-1-yl)propyl, 3-(1,2,4-triazol-4-yl)propyl, 2-(4-pyridyloxy)ethyl, 3-(4-pyridyloxy)propyl, 2-(4-pyridylamino)ethyl, 3-(4-pyridylamino)propyl, 2-(2-(methylimidazol-1-yl)ethyl, 3-(2-methylimidazol-1-yl)propyl, 2-(5-methyl-1,2,4-triazol-1-yl)ethyl, 3-(5-methyl-1,2,4-triazol-1-yl)propyl, morpholino, N-methylpiperazinyl, piperazinyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-(piperazin-1-yl)ethyl, 3-(piperazin-1-yl)propyl, 2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl, 2-methoxyethyl, 3-methoxypropyl, 2-(imidazol-1-yl)ethyl, 2-(1,2,3-triazol-1-yl)ethyl, 2-(1,2,3-triazol-2-yl)ethyl, 3-(imidazol-1-yl)propyl, 3-(1,2,3-triazol-1-yl)propyl, 3-(1,2,3-triazol-2-yl)propyl, 2-thiomorpholinoethyl, 3-thiomorpholinopropyl, 2-(1,1-dioxothiomorpholino)ethyl, 3-(1,1-dioxothiomorpholino)propyl, 2-(2-(oxyethoxy)ethyl, 2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl, 3-(methylsulphinyl)propyl, 3-(methylsulphonyl)propyl, 2-(methylsulphinyl)ethyl, benzyl, 2-sulphamoylethyl or 2-(methylsulphonyl)ethyl.
Especially R13 represents methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl, 2-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl, 2-sulphamoylethyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-(piperazin-1-yl)ethyl, 3-(piperazin-1-yl)propyl, 2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl, (1,3-dioxolan-2-yl)methyl, 2(1,3-dioxolan-2-yl)ethyl, 2-(2-methoxyethylamino)ethyl, 2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl, 3-(2-hydroxyethylamino)propyl, 2-(methylthiazol-4-ylmethyl, 2-acetamidothiazol-4-ylmethyl, 1-methylimidazol-2-ylmethyl, 2-(imidazol-1-yl)ethyl, 2-(1,2,3-triazol-1-yl)ethyl, 2-(1,2,3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl, 2 (1,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl, 3-(4-pyridyl)propyl, 3-(3-pyridyl)propyl, benzyl, 2-(4-pyridyloxy)ethyl, 2-(4-pyridylamino)ethyl, or 2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl.
More especially R13 represents methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl, 2-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl, 2-sulphamoylethyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-(piperazin-1-yl)ethyl, 3-(piperazin-1-yl)propyl, 2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl, (1,3-dioxolan-2-yl)methyl, 2-(1,3-dioxolan-2-yl)ethyl, 2-(2-methoxyethylamino)ethyl, 2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl, 3-(2-hydroxyethylamino)propyl, 2-methylthiazol-4-ylmethyl, 2-acetamidothiazol4-ylmethyl, 1-methylimidazol-2-ylmethyl, 2-(imidazol-1-yl)ethyl, 2-(1,2,3-triazol-1-yl)ethyl, 2-(1,2,3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1yl)ethyl, 2-(1,2,4-triazol-4yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl, 3-(4-pyridyl)propyl, benzyl, 2-(4-pyridyloxy)ethyl, 2-(4-pyridylamino)ethyl, or 2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl.
In particular R1 and R4 are suitably hydrogen.
Examples of preferred groups for R2 include C1-6 alkoxy or cyano, and preferably C1-6alkoxy such as methoxy.
The group R3 is suitably selected from hydrogen or C1-6alkoxy such as methoxy.
Preferably both R2 and R3 are C1-6 alkoxy and arc preferably methoxy.
Particular examples of compounds of formula (I) are listed in Table 1.
Certain compounds of formula (I) are novel and these provide a further aspect of the invention. In particular, the invention provides a compound of formula (IA) which comprises a compound of formula (I), provided that where R5 is bromo, R6 is other than phenyl, methyl substituted phenyl or di-halo substituted phenyl.
Thus Examples of compounds of formula (IA) are compounds of formula (I) where R5 is chloro.
Other compounds of formula (IA) are compounds of formula (I) where R5 is bromo and R6 is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl of 1 to 6 carbon atom groups; or is a pyridinyl pyrimidinyl, ring; wherein the pyridinyl, pyrimidinyl, or phenyl ring may be substituted with one, two or three groups selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenyl, benzoyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, and benzoylamino; or two adjacent substitutents on said, pyridyl or pyrimidinyl ring may be joined together to form a fused ring, which ring may be aromatic or non-aromatic in character and which may contain further heteroatoms, or R6 is a group xe2x80x94R5xe2x80x94Xxe2x80x94R9 where R8, X and R9 are as defined above.
Yet further compounds of formula (IA) are compounds of formula (I) where R6 is phenyl which is substituted with one, two or three groups selected from the group consisting of alkyl of 2-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenyl, benzoyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, and benzoylamino; or two adjacent substitutents on said phenyl ring may be joined together to form a fused ring, which ring may be aromatic or non-aromatic in character and which may contain further heteroatoms
Preferred classes of compound of formula (IA) include those listed above in respect of formula (I).
Compounds of formula (I) are suitably prepared by reacting a compound of formula (III) 
where R1xe2x80x2, R2xe2x80x2, R3xe2x80x2, R4xe2x80x2 represent R1, R2, R3 and R4 respectively as defined in relation to formula (I) or a precursor thereof, R5 is as defined in relation to formula (I), and Zxe2x80x2 is a leaving group, with a compound of formula (IV)
Hxe2x80x94Y(CH2)nR6xe2x80x2xe2x80x83xe2x80x83(IV)
where Y, X, and n are as defined in relation to formula (I), and R6xe2x80x2 is a group R6 as defined in relation to formula (I) or a precursor thereof; and thereafter if necessary or desired converting precursor groups R1xe2x80x2, R2xe2x80x2, R3xe2x80x2, R4xe2x80x2 and R6xe2x80x2 to groups of formula R1, R2, R3, R4 and R6 respectively, or converting a group R1, R2, R3, R4 and R6 to a different such group.
Suitable leaving groups for Zxe2x80x2 include halogen such as bromo or chloro, or a mesylate or tosylate group. In particular Zxe2x80x2 is chloro.
The reaction is suitably carried out in an organic solvent such as an alcohol for example propanol, cyclohexanol, at elevated temperatures, for example of from 50 to 150xc2x0 C., for example at about 105xc2x0 C. or 110xc2x0 C.
Conversion reactions in which precursor groups R1xe2x80x2, R2xe2x80x2, R3xe2x80x2, R4xe2x80x2 are converted to groups of formula R1, R2, R3 and R4 respectively, or groups R1, R2, R3 and R4 are converted to different such group can be carried out using conventional chemistry as described in the literature. Particular precursor groups R1xe2x80x2, R2xe2x80x2, R3xe2x80x2, R4xe2x80x2 are groups of formula R13xe2x80x2xe2x80x94X1xe2x80x94(CH2)x wherein x and X1 are as defined hereinafter, and R13xe2x80x2 is C1-5alkyl which is substituted with halo other than fluoro, and in particular chloro or bromo. The chloro group may readily be converted many other groups R13 as defined in relation to claim 1. Such compounds are novel and form a further aspect of the invention. They may have activity similar to that of compounds of formula (I) in their own right and therefore may be used in place of a compound of formula (I).
Thus the invention further provides a compound of formula (IB) 
where Y, n, R5 and R6 are as defined above and at least one of R1xe2x80x3, R2xe2x80x3, R3xe2x80x3 or R4xe2x80x3 is a group R13xe2x80x2xe2x80x94X1xe2x80x94(CH2)x wherein X7 and x are as above and R13xe2x80x2 is alkyl substituted by chloro or bromo; and the remainder are groups R1, R2, R3 and R4 respectively.
Similarly conversion reactions involving groups R6xe2x80x2 may be effected using conventional chemistry. For example substitutent groups on a group R6 may be changed, for example by changing acids to esters or amides etc.
A further example, to produce compounds of formula (I) where R6 is a group xe2x80x94R8xe2x80x94Xxe2x80x94R9 it to react a compound of formula (V) 
where R1xe2x80x2, R2xe2x80x2, R3xe2x80x2, R4xe2x80x2 are as defined in relation to formula (III) R8, X, Y and n are as defined in relation to formula (I), with a compound of formula (VI)
R9xe2x80x2xe2x80x94Zxe2x80x3xe2x80x83xe2x80x83(VI)
where R9xe2x80x2 is a group R9 as defined in relation to formula (IV) or a precursor thereof and Zxe2x80x3 is a leaving group;
and thereafter if necessary or desired converting precursor groups R1xe2x80x2, R2xe2x80x2, R3xe2x80x2, R4xe2x80x2 and R9xe2x80x2 to groups of formula R1, R2, R3, R4 and R9 respectively, or converting a group R1, R2, R3, R4 and R9 to a different such group. Suitable leaving groups for Zxe2x80x3 include halogen such a bromo or chloro, or a mesylate or tosylate group. Conversion reactions are as described above.
The reaction is suitably carried out in an organic solvent such as DMF at elevated temperatures, for example of from 40 to 120xc2x0 C., for example at about 80xc2x0 C.
Preferably however, R1, R2, R3, R4xe2x80x2, and R6 are groups R1, R2, R3, R4 and R6 respectively and so no subsequent processing is required.
Certain compounds of formula (III) are disclosed in WO98/13350 and others can be prepared from known compounds by analogous methods. For example, they are suitably prepared by reacting a compound of formula (V) 
where R1, R2, R3, R4 and R5 are as defined in relation to formula (I), with a compound of formula (VI)
Zxe2x80x2xe2x80x94R20xe2x80x83xe2x80x83(VI)
where Zxe2x80x2 is as defined above and R20 is a further leaving group such as sulphonylchloride. A particular example of a compound of formula (VI) is thionyl chloride.
The reaction is suitably effected in an organic solvent such as dimethylformamide, at elevated temperatures for example of from 50 to 150xc2x0 C., and conveniently at the reflux temperature of the solvent.
Compounds of formula (V) may be prepared by chlorination or bromination of a compound of formula (VII) 
where R1, R2, R3 and R4 are as defined in relation to formula (I).
Halogenation can be effected using known halogenating agents such as N-halosuccinimides. The reaction is suitably effected in an organic solvent such as carbon tetrachloride. It may advantageously be carried out in the presence of a radical initiator such as azobisisobutyronitrile. Elevated temperatures of from 40 to 76xc2x0 C. are suitably employed. Where R5 is bromine, the reaction can also be effected using bromine in aqueous solution in the presence of a base such as sodium hydroxide. A suitable temperature for such a reaction would be in the range of from 20 to 25xc2x0 C.
Compounds of formula (VII) are either known compounds (see for example WO99/00372 and WO9847873, or they can be prepared from known compounds by conventional methods. Compounds of formula (IV) are also either known compounds (see for example Rev. Chim. (Bucharest (1988), 39(6), 477-82, DD110651:74.01.05) or they can be prepared from known compounds by conventional methods.
Compounds of the invention are useful in the inhibition of MEK enzyme activity and can be used in the treatment of proliferative disease. They will suitably be in the form of a pharmaceutical composition, in combination with a pharmaceutically acceptable carrier. Such compositions form a further aspect of the invention.
The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal track, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.
Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxyethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavouring and preservative agents.
Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.
Suppository formulations may be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols.
Topical formulations, such as creams, ointments, gels and aqueous or oily solutions or suspensions, may generally be obtained by formulating an active ingredient with a conventional, topically acceptable, vehicle or diluent using conventional procedure well known in the art.
Compositions for administration by insufflation may be in the form of a finely divided powder containing particles of average diameter of, for example, 30xcexc or much less, the powder itself comprising either active ingredient alone or diluted with one or more physiologically acceptable carriers such as lactose. The powder for insufflation is then conveniently retained in a capsule containing, for example, 1 to 50 mg of active ingredient for use with a turbo-inhaler device, such as is used for insufflation of the known agent sodium cromoglycate.
Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
For further information on Formulation the reader is referred to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.
The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent to compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.
The size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine. As mentioned above, compounds of the Formula I are useful in treating diseases or medical conditions which are due alone or in part to the effects of MEK enzymes.
In using a compound of the Formula I for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.5 mg to 75 mg per kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, 0.5 mg to 30 mg per kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.5 mg to 25 mg per kg body weight will be used. Oral administration is however preferred.
In a further aspect, the invention provides a method of treating proliferative disease by administering a compound of formula (I) as described above, or a pharmaceutical composition as described above.
Yet a further aspect of the invention provides the use of a compound of formula (I) as defined above, in the preparation of a medicament for use in the inhibition of MEK enzyme activity and in particular for the treatment of proliferative disease such as cancer.